1. Field of the Invention
This invention relates to a novel lipid emulsion having the activity of potentiating the anti-cancer activity of an anti-cancer agent, a method of potentiating the activities of anti-cancer agents by using it with the lipid emulsion, and to a method of treating cancer occurring in a warm-blooded animal by administering the novel lipid emulsion in combination with anti-cancer agents to the warm-blooded animal.
2. Description of the Prior Art
N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine of the following formula (II) ##STR2## is a known compound.
The compound of formula (II) is described in the patent literature as one of a series of isoprenylamine derivatives having antiviral and antitumoral activities (see, for example, Japanese Laid-Open Patent Publication No. 192339/1982 and its corresponding U.S. Pat. Nos. 4645862, 4658063, 4700002 and 4323008).
In recent years various carcinostats and anti-cancer agents against solid tumors such as lung cancer, stomach cancer, breast cancer, bladder cancer and testicular tumor or tumors in the hematopoietic organs such as leukemia and malignant lymphoma have been developed, but no drug has yet come out which can completely cure or prevent these malignant tumors. For example, cyclophosphamide (CPA), melphalan (MPL), nimustine (ACNU), carboquone (CQ), vincristine (VCR), vinblastine (VLB), vindesine (VDS), bleomycin (BLM), 5-fluorouracil (5-FU), adriamycin (ADM), cisplatin (CDDP), actinomycin D (ACD), methotrexate (MTX), aclarubicin (ACR), toyomycin (TM), neocartinostatin (NCS), and ifosfamide (Ifos) have been used heretofore therapeutically as anti-cancer agents (the parenthesized letters show abbreviated designations) which may sometimes be used hereinafter). These drugs are used selectively and specifically in various areas because of their inherent anti-cancer spectra. For example, adriamycin (ADM) has a broader anti-cancer spectrum than other drugs, and is used against breast cancer, bladder cancer, lung cancer, testicular tumor, malignant lymphoma, and acute leukemia. However, the efficacy of ADM on these diseases is limited, and cancer cells showing resistance to ADM have appeared. A further cumbersome and complex problem is that other drugs do not show an anti-cancer action on these ADM-resistant cancer cells.
The appearance of drug-resistant tumor cells also becomes a problem with drugs other than ADM.
Recently, searching for compounds effective on these drug-resistant tumor cells was considered, and it has so far been found that when N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine itself or its hydrochloride is combined with ADM, the pharmacological efficacy of ADM can be potentiated, particularly against ADM-resistant tumor cells. This finding was applied for a patent (Japanese Laid-Open Patent Publication No. 200913/1986).
The present inventors further made investigations in order to overcome the problem of the drug-resistance of tumor cells, and determined that an acid salt, especially a malate, of N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine of formula (II) above has excellent anti-cancer activity as compared with the compound (II) and it hydrochloride and can potentiate the pharmacological efficacy of not only adriamycin but also other anti-cancer agents, particularly the anti-cancer activity of these compounds on drug-resistant tumor cells, and that this activity has some degree of specificity.
The present inventors have further found that when the malate of compound (II) is administered in a form incorporated in lipid microspheres by applying the drug delivery system (DDS), the lipid microspheres are transferred selectively to tumor cells, and the incorporated malate exhibits its effect in situ, and that this offers an effective therapeutic method.